Overweight/obese Individuals are at increased risk of being insulin resistant, and more likely to develop cardiovascular disease (CVD), type 2 diabetes (2DM), and obstructive sleep apnea (OSA). CVD and 2DM occur commonly in patients with OSA, leading to the view that CVD and 2DM are secondary to OSA. However, there is evidence that insulin resistance can lead to the development of OSA, similar to the pathogenesis of 2DM and CVD. We propose a new explanation for the relationships outlined above; insulin resistance not only contributes to the etiology of OSA, but is the common feature explaining why OSA, 2DM, and CVD form a clinical cluster. We also postulate that treatment with pioglitazone (PIO) in insulin resistant (IR) patients with OSA will enhance insulin sensitivity, associated with clinical improvement and decreases in cardio-metabolic risk. This proposal has three primary goals. 1) A comparison of specific measurements of insulin action, insulin secretion, and multiple cardio-metabolic risk factors in overweight patients with OSA with a weight-matched control group; predicting that subjects with OSA will be more insulin resistant, and at greater cardio-metabolic risk. 2) PIO, or placebo, will be given to IR patients with OSA, and we predict that insulin sensitivity will be enhanced in PlO-treated patients, associated with clinical improvement in OSA, a return towards normal of insulin secretion; and a decrease in cardio-metabolic risk. 3) The same experimental approaches will be used to evaluate the clinical and/or metabolic benefits of adding continuous positive airway pressure (CPAP) to PlO-treated and placebo-treated patients with OSA.; predicting that CPAP alone will not have the same overall benefits of PIO, but will enhance those of PIO. A secondary goal is to evaluate the hypothesis that changes in the activity of apelin, the endogenous ligand for the APJ receptor, serves as an important mechanistic link between excess adiposity and insulin resistance. Apelin, and its receptor, are located in adipose tissue, and appear to be involved in maintenance of normal insulin sensitivity. We will test the hypothesis that apelin contributes significantly to the relationship between excess adiposity and insulin resistance by comparing plasma apelin levels in patients with OSA vs. the control group, as well as after the two interventions in IR patients with OSA. Adipose tissue biopsies will also be obtained in IR with OSA before and after each of the two interventions to evaluate changes in apelin modulation of glucose and lipid metabolism at the tissue level. RELEVANCE: Obstructive sleep apnea (OSA) is more common in obese individuals, and is associated with increased risk of type 2 diabetes and cardiovascular disease (CVD).The hypothesis underlying this research proposal is that resistance to insulin action accounts for the clustering of OSA, type 2 diabetes and CVD. If this view can be validated it will dramatically change current understanding of the cause and the treatment of OSA. (End of Abstract)